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Preexposure Prophylaxis for the Prevention of HIV Infection in the United States – 2014 Clinical Practice Guideline Page 2 of 67 Table of Contents
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PREEXPOSURE PROPHYLAXIS FOR THE PREVENTION OF HIV INFECTION IN THE UNITED STATES - 2014 A CLINICAL PRACTICE GUIDELINE

Preexposure Prophylaxis for the Prevention of HIV Infection in the United States – 2014 Clinical Practice Guideline

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Table of Contents List of Tables, Figures, and Boxes ................................................................................................5 Abbreviations (In Guideline and Provider Supplement) ...........................................................7 Summary .........................................................................................................................................9 Introduction ..................................................................................................................................12 Evidence of Need for Additional HIV Prevention Methods.....................................................13 Evidence of the Safety and Efficacy of Antiretroviral Prophylaxis ........................................14 Published Trials of Antiretroviral Preexposure Prophylaxis Among Men Who Have Sex with Men ..........................................................................................................................................14 iPrEx (Preexposure Prophylaxis Initiative) Trial ...........................................................................14 US MSM Safety Trial ..............................................................................................................15

Published Trials of Antiretroviral Preexposure Prophylaxis Among Heterosexual Men and Women .....................................................................................................................................16 Partners PrEP Trial..................................................................................................................16 TDF2 Trial ............................................................................................................................16 FEM-PrEP Trial .....................................................................................................................17 Phase 2 Trial of Preexposure Prophylaxis with Tenofovir Among Women in Ghana, Cameroon, and Nigeria..................................................................................................................................17 VOICE (Vaginal and Oral Interventions to Control the Epidemic) Trial .............................................18

Published Trial of Antiretroviral Preexposure Prophylaxis Among Injection Drug Users .....19 Bangkok Tenofovir Study (BTS)................................................................................................19

Identifying Indications for PrEP ................................................................................................26 Assessing Risk of Sexual HIV Acquisition .............................................................................26 Assessing Risk of HIV Acquisition Through Injection Practices ............................................29 Laboratory Tests and Other Diagnostic Procedures ................................................................30 HIV testing ............................................................................................................................30

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Acute HIV Infection ................................................................................................................31 Renal function ........................................................................................................................33 Hepatitis Serology ...................................................................................................................34

Providing PrEP ............................................................................................................................35 Goals of PrEP Therapy ............................................................................................................35 Indicated Medication ...............................................................................................................36 What Not to Use.......................................................................................................................37 Time to achieving protection .................................................................................................377 Managing side effects ..............................................................................................................38 Clinical Follow-up and Monitoring .......................................................................................388 Optional Assessments ..............................................................................................................39 Bone Health ...........................................................................................................................39 Therapeutic drug monitoring .....................................................................................................39

Persons with Documented HIV Infection ..................................................................................39 Discontinuing PrEP .....................................................................................................................40 Special Clinical Considerations ..................................................................................................40 Women who become pregnant or breastfeed while taking PrEP medication ..........................40 Patients with Chronic Active Hepatitis B Virus Infection .......................................................41 Patients with Chronic Renal Failure ........................................................................................42 Adolescent Minors101 ...............................................................................................................42 Nonoccupational Postexposure Prophylaxis ............................................................................43 Improving Medication Adherence..............................................................................................43 Reducing HIV Risk Behaviors ....................................................................................................45 Financial Case-Management Issues for PrEP ...........................................................................47 Decision Support, Training and Technical Assistance .............................................................47

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Related DHHS Guidelines ...........................................................................................................48 APPENDICES ..............................................................................................................................49 Appendix 1 HIV Test Tables ...................................................................................................50 Appendix 2 Grading of Strength of Recommendations and Quality of Evidence ...................52 Appendix 3 Participants in PrEP Guidelines Development and Review .................................54 References .....................................................................................................................................58

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List of Tables, Figures, and Boxes Table 1 Summary of Guidance for PrEP Use .........................................................................11 Table 2 PrEP Evidence Summary—GRADE Overall Evidence Quality .............................21 Table 3 PrEP Evidence Summary— HIV Incidence Findings ..............................................22 Table 4 PrEP Evidence Summary—Measures of Efficacy by Medication Adherence .......23 Table 5 PrEP Evidence Summary— Safety and Toxicity .....................................................24 Table 6 PrEP Evidence Summary— HIV Resistance Findings.............................................25 Table 7 Clinical Signs and Symptoms of Acute (Primary) HIV Infection ...........................32 Table 8 Hepatitis Screening Serology ......................................................................................35 Table 9 Recommended Oral PrEP Medications .....................................................................36 Table 10 PrEP Medication Drug Interactions..........................................................................37 Table 11 HIV Testing— FDA-Approved Rapid Tests Used for Point-of-Care Testing or in Clinicians Offices ..........................................................................................................50 Table 12 HIV Testing—FDA-Approved Diagnostic Laboratory Based HIV Tests (CLIAHigh Complexity Tests) ................................................................................................51 Table 13 Rating Scheme for Recommendations .....................................................................52 Table 14 Criteria for Rating Quality of Scientific Evidence ..................................................53 Figure Documenting HIV Status .............................................................................................33 Box A

Risk Behavior Assessments..........................................................................................26

Box A1 Risk Behavior Assessment for MSM .........................................................................26 Box A2 Risk Behavior Assessment for Heterosexually Active Men and Women ..................27 Box A3 Risk Behavior Assessment for Injection Drug Users .................................................30 Box B

Recommended Indications for PrEP Use ..................................................................28

Box B1 Recommended Indications for PrEP Use by MSM ....................................................28 Box B2 Recommended Indications for PrEP Use by Heterosexually Active Men and Women ..................................................................................................................................................29 Box B3 Indications for PrEP Use by Injection Drug Users .....................................................30

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Box C

Cockcroft-Gault Formulas ..........................................................................................34

Box D

Key Components of Medication Adherence Counseling ..........................................45

Box E

Key Components of Behavioral Risk Reduction Counseling ...................................47

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Abbreviations (In Guideline and Provider Supplement) ACTG AHRQ AIDS BMD CDC CPT DEXA DHAP DHHS eCrCl EIA FDA FHI FTC GEM GLIA GRADE HBV HCV HIV HRSA ICD IDU IFA IHS MSM MTN NCHHSTP NGC NIAID NIH nPEP NSAID NQMC OHAP ONAP ONDCP OPA PCR

AIDS Clinical Trials Group Agency for Healthcare Research and Quality acquired immunodeficiency syndrome bone mineral density Centers for Disease Control and Prevention common procedural terminology dual-emission X-ray absorptiometry Division of HIV/AIDS Prevention, CDC Department of Health and Human Services estimated creatinine clearance rate (ml/min) enzyme-linked immunoassay Food and Drug Administration Family Health International emtricitabine (trade name Emtriva) Guidelines Elements Model GuideLine Implementability Appraisal Grading of Recommendations Assessment, Development and Evaluation hepatitis B virus hepatitis C virus human immunodeficiency virus Health Resources and Services Administration International Classification of Diseases injection drug users (also called PWID) indirect immunofluorescence assay Indian Health Service men who have sex with men Microbicide Trials Network National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention National Guidelines Clearinghouse National Institute of Allergy and Infectious Diseases National Institutes of Health nonoccupational postexposure prophylaxis non-steroidal anti-inflammatory drug National Quality Measures Clearinghouse Office of HIV/AIDS Policy, DHHS Office of National AIDS Policy Office of National Drug Control Policy Office of Population Affairs, DHHS polymerase chain reaction

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PEP PHS PWID PrEP SAMHSA STD STI TB TDF TDM UNAIDS VA WHO

postexposure prophylaxis (U.S.) Public Health Service persons who inject drugs (also called IDU) preexposure prophylaxis Substance Abuse and Mental Health Services Administration sexually transmitted disease sexually transmitted infection tuberculosis tenofovir disoproxil fumarate (trade nanme Viread®) therapeutic drug monitoring Joint United National Programme on HIV/AIDS Veterans Administration World Health Organization

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Summary Preexposure Prophylaxis for HIV Prevention in the United States - 2013: A Clinical Practice Guideline provides comprehensive information for the use of daily oral antiretroviral preexposure prophylaxis (PrEP) to reduce the risk of acquiring HIV infection in adults. The key messages of the guideline are as follows: 



 



1

Daily oral PrEP with the fixed-dose combination of tenofovir disoproxil fumarate (TDF) 300 mg and emtricitabine (FTC) 200 mg has been shown to be safe and effective in reducing the risk of sexual HIV acquisition in adults; therefore, o PrEP is recommended as one prevention option for sexually-active adult MSM (men who have sex with men) at substantial risk of HIV acquisition (IA)1 o PrEP is recommended as one prevention option for adult heterosexually active men and women who are at substantial risk of HIV acquisition. (IA) o PrEP is recommended as one prevention option for adult injection drug users (IDU) at substantial risk of HIV acquisition. (IA) o PrEP should be discussed with heterosexually-active women and men whose partners are known to have HIV infection (i.e., HIV-discordant couples) as one of several options to protect the uninfected partner during conception and pregnancy so that an informed decision can be made in awareness of what is known and unknown about benefits and risks of PrEP for mother and fetus (IIB) Currently the data on the efficacy and safety of PrEP for adolescents are insufficient. Therefore, the risks and benefits of PrEP for adolescents should be weighed carefully in the context of local laws and regulations about autonomy in health care decision-making by minors. (IIIB) Acute and chronic HIV infection must be excluded by symptom history and HIV testing immediately before PrEP is prescribed. (IA) The only medication regimen approved by the Food and Drug Administration and recommended for PrEP with all the populations specified in this guideline is daily TDF 300 mg co-formulated with FTC 200 mg (Truvada) (IA) o TDF alone has shown substantial efficacy and safety in trials with IDUs and heterosexually active adults and can be considered as an alternative regimen for these populations, but not for MSM, among whom its efficacy has not been studied. (IC) o The use of other antiretroviral medications for PrEP, either in place of or in addition to TDF/FTC (or TDF) is not recommended. (IIIA) o The prescription of oral PrEP for coitally-timed or other noncontinuous daily use is not recommended. (IIIA) HIV infection should be assessed at least every 3 months while patients are taking PrEP so that those with incident infection do not continue taking it. The 2-drug regimen of TDF/FTC

See Appendix 2, Grading of Strength of Recommendations and Quality of Evidence (Tables 13-14)

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is inadequate therapy for established HIV infection, and its use may engender resistance to either or both drugs. (IA) Renal function should be assessed at baseline and monitored at least every 6 months while patients are taking PrEP so that those in whom renal failure is developing do not continue to take it. (IIIA) When PrEP is prescribed, clinicians should provide access, directly or by facilitated referral, to proven effective risk-reduction services. Because high medication adherence is critical to PrEP efficacy but was not uniformly achieved by trial participants, patients should be encouraged and enabled to use PrEP in combination with other effective prevention methods. (IIIA)

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Table 1: Summary of Guidance for PrEP Use

Detecting substantial risk of acquiring HIV infection

Men Who Have Sex with Men

Heterosexual Women and Men

Injection Drug Users

HIV-positive sexual partner Recent bacterial STI High number of sex partners History of inconsistent or no condom use Commercial sex work

HIV-positive sexual partner Recent bacterial STI High number of sex partners History of inconsistent or no condom use Commercial sex work

HIV-positive injecting partner Sharing injection equipment Recent drug treatment (but currently injecting)

In high-prevalence area or network Clinically eligible

Prescription Other services

Documented negative HIV test result before prescribing PrEP No signs/symptoms of acute HIV infection Normal renal function; no contraindicated medications Documented hepatitis B virus infection and vaccination status Daily, continuing, oral doses of TDF/FTC (Truvada), ≤90-day supply Follow-up visits at least every 3 months to provide the following: HIV test, medication adherence counseling, behavioral risk reduction support, side effect assessment, STI symptom assessment At 3 months and every 6 months thereafter, assess renal function Every 6 months, test for bacterial STIs Do oral/rectal STI testing

Assess pregnancy intent Pregnancy test every 3 months

STI: sexually transmitted infection

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Access to clean needles/syringes and drug treatment services

Introduction Recent findings from several clinical trials have demonstrated safety1 and a substantial reduction in the rate of HIV acquisition for men who have sex with men (MSM)2, men and women in heterosexual HIV-discordant couples3, and heterosexual men and women recruited as individuals4 who were prescribed daily oral antiretroviral preexposure prophylaxis (PrEP) with a fixed-dose combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC). In addition, one clinical trial among injection drug users (IDU)5 and one among men and women in heterosexual HIV-discordant couples3 have demonstrated substantial efficacy and safety of daily oral PrEP with TDF alone. The demonstrated efficacy of PrEP was in addition to the effects of repeated condom provision, sexual risk-reduction counseling, and the diagnosis and treatment of sexually transmitted infection (STI), all of which were provided to trial participants, including those in the drug treatment group and those in the placebo group. In July 2012, after reviewing the available trial results, the U.S. Food and Drug Administration (FDA) approved an indication for the use of Truvada† (TDF/FC) “in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk”6,7. On the basis of these trial results and the FDA approval, the U.S. Public Health Service recommends that clinicians evaluate their male and female patients who are sexually active or who are injecting illicit drugs and consider offering PrEP as one prevention option to those whose sexual or injection behaviors and epidemiologic context place them at substantial risk of acquiring HIV infection. The evidence base for these recommendations is derived from a systematic search and review of published literature. To identify all PrEP safety and efficacy trials pertaining to the prevention of sexual and injection acquisition of HIV, a search of the clinical trials registry (http://www.clinicaltrials.gov) was performed by using combinations search terms (preexposure prophylaxis, pre-exposure prophylaxis, PrEP, HIV, Truvada, tenofovir, and antiretroviral). In addition, the same search terms were used to search conference abstracts for major HIV conferences (e.g., International AIDS Conference, Conference on Retroviruses and Opportunistic Infections) for the years 2009-2013. These same search terms were used to search PubMed and Web of Science databases for the years 2006-2013. Finally, a review of references from published PrEP trial data and the data summary prepared by FDA for its approval decision8 confirmed that no additional trial results were available. This publication provides a comprehensive clinical practice guideline for the use of PrEP for the prevention of HIV infection in the United States. It incorporates and extends information provided in interim guidance for PrEP use with MSM9, with heterosexually active adults10, and with IDU (also called persons who injection drugs [PWID])11. Currently, prescribing daily oral †

Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services. Preexposure Prophylaxis for the Prevention of HIV Infection in the United States – 2014 Clinical Practice Guideline Page 12 of 67

PrEP with TDF/FTC is recommended as one prevention option for MSM, heterosexual men, heterosexual women, and IDU at substantial risk of HIV acquisition. As the results of additional PrEP clinical trials and studies in these and other populations at risk of HIV acquisition become known, this guideline will be updated. The intended users of this guideline include  primary care clinicians who provide care to persons at risk of acquiring HIV infection  clinicians who provide substance abuse treatment  infectious disease and HIV treatment specialists who may provide PrEP or serve as consultants to primary care physicians about the use of antiretroviral medications  health program policymakers.

Evidence of Need for Additional HIV Prevention Methods Approximately 50,000 people in the United States are infected with HIV each year12. From 2008 through 2010, HIV incidence remained stable or declined among IDU and heterosexuals of all races and Hispanic/Latino ethnicity, but incidence increased among MSM (12% increase), especially among adolescent and young adult MSM (aged 13-24 years) (22% increase)12. The greatest number of new HIV infections among MSM occurred in young African American MSM (4,800). In 2010, 63% of the estimated 47,500 new infections were attributed to male-male sexual activity without injection drug use, 4% to male-male sexual activity with injection drug use, 25% to male-female sexual contact without injection drug use, and 8% to injection drug use. Among the 25% of persons newly infected through heterosexual activity, 66% were AfricanAmerican women and men. These data indicate a need for additional methods of HIV prevention to further reduce new HIV infections, especially (but not exclusively) among young adult and adolescent MSM of all races and Hispanic/Latino ethnicity and for African American heterosexuals (populations with higher HIV prevalence and at higher risk of HIV infection among those without HIV infection).

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Evidence of the Safety and Efficacy of Antiretroviral Prophylaxis The biological plausibility and the short-term safety of antiretroviral use to prevent HIV acquisition in other exposure situations have been demonstrated in 2 studies conducted prior to the PrEP trials. In a randomized placebo-controlled trial, perinatal transmission was reduced 68% among the HIV-infected women who received zidovudine during pregnancy and labor and whose infants received zidovudine for 6 weeks after birth13. That is, these infants received both preexposure and postexposure prophylaxis. In 1995, investigators used case-control surveillance data from health- care workers to demonstrate that zidovudine provided within 72 hours after percutaneous exposure to HIV-infected blood and continued for 28 days (PEP, or postexposure prophylaxis) was associated with an 81% reduction in the risk of acquiring HIV infection14-16. Evidence from these human studies of blood-borne and perinatal transmission as well as studies of vaginal and rectal exposure among animals17-19 suggested that PrEP (using antiretroviral drugs) could reduce the risk of acquiring HIV infection from sexual and drug-use exposures. Clinical trials were launched to evaluate the safety and efficacy of PrEP in populations at risk of HIV infection through several routes of exposure. The results of completed trials published as of August 2013 are summarized below. See also Tables 2-6.

P UBLISHED T RIALS OF A NTIRETROVIRAL P REEXPOSURE P ROPHYLAXIS A MONG M EN W HO H AVE S EX WITH M EN IPREX

(P REEXPOSURE P ROPHYLAXIS I NITIATIVE ) T RIAL

The iPrEx study2 was a phase 3, randomized, double-blind, placebo-controlled trial conducted in Peru, Ecuador, Brazil, Thailand, South Africa, and the United States among men and male-tofemale transgender adults who reported sex with a man during the 6 months preceding enrollment. Participants were randomly assigned to receive a daily oral dose of either the fixeddose combination of TDF and FTC or a placebo. All participants (drug and placebo groups) were seen every 4 weeks for an interview, HIV testing, counseling about risk- reduction and adherence to PrEP medication doses, pill count, and dispensing of pills and condoms. Analysis of data through May 1, 2010, revealed that after the exclusion of 58 participants (10 later determined to be HIV- infected at enrollment and 48 who did not have an HIV test after enrollment), 36 of 1,224 participants in the TDF/FTC group and 64 of 1,217 in the placebo group had acquired HIV infection. Enrollment in the TDF/FTC group was associated with a 44% reduction in the risk of HIV acquisition (95% CI, 15-63). The reduction was greater in the as-treated analysis: at the visits at which adherence was ≥50% (by self-report and pill count/dispensing), the reduction in HIV acquisition was 50% (95% CI, 18-70). The reduction in the risk of HIV acquisition was 73% at visits at which self-reported adherence was ≥90% (95% CI, 41-88) during the preceding 30 days. Among participants randomly assigned to the TDF/FTC group, plasma and intracellular drug-level testing was performed for all those who acquired HIV infection during the trial and for a matched subset who remained HIV- uninfected: a 92% reduction in the risk of HIV Preexposure Prophylaxis for the Prevention of HIV Infection in the United States – 2014 Clinical Practice Guideline Page 14 of 67

acquisition (95% CI, 40-99) was found in participants with detectable levels of TDF/FTC versus those with no drug detected. Generally, TDF/FTC was well tolerated, although nausea in the first month was more common among participants taking medication than among those taking placebo (9% versus 5%). No differences in severe (grade 3) or life-threatening (grade 4) adverse laboratory events were observed between the active and placebo group, and no drug-resistant virus was found in the 100 participants infected after enrollment. Among 10 participants who were HIV-negative at enrollment but later found to have been infected before enrollment, FTC-resistant virus was detected in 2 of 2 men in the active group and 1 of 8 men in the placebo group. Compared to participant reports at baseline, over the course of the study participants in both the TDF/FTC and placebo groups reported fewer total numbers of sex partners with whom the participants had receptive anal intercourse and higher percentages of partners who used condoms. US MSM S AFETY T RIAL The US MSM Safety Trial1 was a phase 2 randomized, double-blind, placebo-controlled study of the clinical safety and behavioral effects of TDF for HIV prevention among 400 MSM in San Francisco, Boston, and Atlanta. Participants were randomly assigned 1:1:1:1 to receive daily oral TDF or placebo immediately or after a 9- month delay. Participants were seen for follow-up visits 1 month after enrollment and quarterly thereafter. Among those without directed drug interruptions, medication adherence was high: 92% by pill count and 77% by pill bottle openings recorded by Medication Event Monitoring System (MEMS) caps. Temporary drug interruptions and the overall frequency of adverse events did not differ significantly between TDF and placebo groups. In multivariable analyses, back pain was the only adverse event associated with receipt of TDF. In a subset of men at the San Francisco site (n=184) for whom bone mineral density (BMD) was assessed, receipt of TDF was associated with small decrease in BMD (1% decrease at the femoral neck, 0.8% decrease for total hip)20. TDF was not associated with reported bone fractures at any anatomical site. Among 7 seroconversions, no HIV with mutations associated with TDF resistance was detected. No HIV infections occurred while participants were being given TDF; 3 occurred in men while taking placebo, 3 occurred among men in the delayed TDF group who had not started receiving drug; 1 occurred in a man who had been randomly assigned to receive placebo and who was later determined to have had acute HIV infection at the enrollment visit. Daily oral PrEP with TDF/FTC is recommended as one HIV prevention option for sexuallyactive MSM at substantial risk of HIV acquisition because the iPrEx trial presents evidence of its safety and efficacy in this population, especially when medication adherence is high. (IA)

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P UBLISHED T RIALS OF A NTIRETROVIRAL P REEXPOSURE P ROPHYLAXIS A MONG H ETEROSEXUAL M EN AND W OMEN P ARTNERS P R EP T RIAL The Partners PrEP trial3,21 was a phase 3 randomized, double-blind, placebo-controlled study of daily oral TDF/FTC or TDF for the prevention of acquisition of HIV by the uninfected partner in 4,758 HIV-discordant heterosexual couples in Uganda and Kenya. The trial was stopped after an interim analysis in mid-2011 showed statistically significant efficacy in the medication groups (TDF/FTC or TDF) compared with the placebo group. In 48% of couples, the infected partner was male. HIV-positive partners had a median CD4 count of 495 cells/µL and were not being prescribed antiretroviral therapy because they were not eligible by local treatment guidelines. Participants had monthly follow-up visits and the study drug was discontinued among women who became pregnant during the trial. Adherence to medication was very high: 98% by pills dispensed, 92% by pill count, and 82% by plasma drug-level testing among randomly selected participants in the TDF and TDF/FTC study groups. Rates of serious adverse events and serum creatinine or phosphorus abnormalities did not differ by study group. Modest increases in gastrointestinal symptoms and fatigue were reported in the antiretroviral medication groups compared with the placebo group, primarily in the first month of use. Among participants of both sexes combined, efficacy estimates for each of the 2 antiretroviral regimens compared with placebo were 67% (95% CI, 44-81) for TDF and 75% (95% CI, 55-87) for TDF/FTC. Among women, the estimated efficacy was 71% for TDF and 66% for TDF/FTC. Among men, the estimated efficacy was 63% for TDF and 84% for TDF/FTC. Efficacy estimates by drug regimen were not statistically different among men, women, men and women combined, or between men and women. In a Partners PrEP substudy that measured plasma TDF levels among participants randomly assigned to receive TDF/FTC, detectable drug was associated with a 90% reduction in the risk of HIV acquisition. TDF- or FTC- resistant virus was detected in 3 of 14 persons determined to have been infected when enrolled (2 of 5 in the TDF group; 1 of 3 in the TDF/FTC group)8. No TDF or FTC resistant virus was detected among those infected after enrollment. Among women, the pregnancy rate was high (10.3 per 100 person –years) and rates did not differ significantly between the study groups. TDF2 T RIAL The Botswana TDF2 Trial22, a phase 2 randomized, double-blind, placebo-controlled study of the safety and efficacy of daily oral TDF/FTC, enrolled 1,219 heterosexual men and women in Botswana, and follow-up has been completed. Participants were seen for monthly follow-up visits, and study drug was discontinued in women who became pregnant during the trial.

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Among participants of both sexes combined, the efficacy of TDF/FTC was 62% (22%-83%). Efficacy estimates by sex did not statistically differ from each other or from the overall estimate, although the small number of endpoints in the subsets of men and women limited the statistical power to detect a difference. Compliance with study visits was low: 33.1% of participants did not complete the study per protocol. However, many were re-engaged for an exit visit, and 89.3% of enrolled participants had a final HIV test. Among 3 participants later found to have been infected at enrollment, TDF/FTC-resistant virus was detected in 1 participant in the TDF/FTC group and a low level of TDF/FTC-resistant virus was transiently detected in 1 participant in the placebo group. No resistant virus was detected in the 33 participants who seroconverted after enrollment. Medication adherence by pill count was 84% in both groups. Nausea, vomiting, and dizziness occurred more commonly, primarily during the first month of use, among those randomly assigned to TDF/FTC than among those assigned to placebo. The groups did not differ in rates of serious clinical or laboratory adverse events. Pregnancy rates and rates of fetal loss did not differ by study group. FEM-P R EP T RIAL The FEM-PrEP trial23 was a phase 3 randomized, double-blind, placebo-controlled study of the HIV prevention efficacy and clinical safety of daily TDF/FTC among heterosexual women in South Africa, Kenya, and Tanzania. Participants were seen at monthly follow-up visits, and study drug was discontinued among women who became pregnant during the trial. The trial was stopped in 2011, when an interim analysis determined that the trial would be unlikely to detect a statistically significant difference in efficacy between the two study groups. Adherence was low in this trial: study drug was detected in plasma samples of 50% 50% (18–70%) >90% 73% (41–88%) NR 100% (87–100%)

Efficacy by Blood Detection of Drug Measures a 92% (40–99%)

TDF: 86% (67–94%) TDF/FTC: 90% (58–98%) NR

NR

TDF detected: 85%b

NR

NR

NR

NR

NR

NR

NR

49%

NR

56% (-19 to 86%) c

74% (17–94%)

NR, not reported.

a

Tenofovir detection assays were done in subsets of persons randomly assigned to receive TDF or TDF/FTC Finding not statistically significant c Among participants on directly observed therapy b

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Table 5: Evidence Summary— Safety and Toxicity Outcome Analyses Study

Agent

Control

Grade 3/4 Adverse Clinical Eventsa iPrEx TDF2 West African Trial

52 events 9 events NR

59 events 10 events NR

Grade 3/4 Adverse Laboratory Events a iPrEx TDF2 West African Trial

59 events 32 events 1 event

48 events 32 events 5 events

Grade 3/4 Adverse Events (Clinical and Laboratory)a Partners PrEP TDF: 323 events TDF/FTC: 337 events FEM-PrEP NR US MSM Safety Trial 36 events VOICE NR BTS 175 events

307 events NR 26 events NR 173 events

NR, not reported.

a

RDBPCT = randomized, double-blind, prospective clinical trial

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Table 6: Evidence Summary— HIV Resistance Findings (TDF or FTC Drug Resistant Virus Detected) Outcome Analyses Study iPrEx US MSM Safety Trial Partners PrEP

TDF2

FEM-PrEP West African Trial VOICE BTS

Agent 2 resistant viruses among 2 persons infected at baseline 0 resistant viruses among 36 persons infected after baseline 0 resistant viruses among 3 persons infected after baseline (in delayed arm before starting drug) 2 resistant viruses among 5 persons infected at baseline and randomly assigned to TDF 1 resistant virus among 3 persons infected at baseline and randomly assigned to TDF/FTC 0 resistant viruses among 27 persons infected after baseline 1 resistant virus in 1 person infected at baseline 0 resistant viruses among 9 persons infected after baseline

Control 1 resistant virus among 8 persons infected at baseline 0 resistant viruses among 64 persons infected after baseline 1 resistant virus among 1 person infected at baseline 0 resistant viruses among 3 persons infected after baseline 0 resistant viruses among 6 persons infected at baseline 0 resistant viruses among 51 persons infected after baseline

1 resistant virus in 1 person infected at baseline (very low frequency and transient detection) 0 resistant viruses among 24 persons infected after baseline 4 resistant viruses among 33 persons infected after baseline 1 resistant virus in 35 persons infected after baseline 0 resistant viruses among 2 persons infected while on TDF NR NR — 0 resistant viruses among 49 persons infected after baseline

NR, not reported.

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Identifying Indications for PrEP Taking a sexual history is recommended for all adult and adolescent patients as part of ongoing primary care, but the sexual history is often deferred because of urgent care issues, provider discomfort, or anticipated patient discomfort. This deferral is common among providers of primary care29, STI care,30 and HIV care31-33. Routinely taking a sexual history is a necessary first step to identify which patients in a clinical practice are having sex with same-sex partners, which are having sex with opposite-sex partners, and what specific sexual behaviors may place them at risk for, or protect them from, HIV acquisition. The clinician can introduce this topic by stating that taking a brief sexual history is routine practice, go on to explain that the information is necessary to the provision of individually appropriate sexual health care, and close by reaffirming the confidentiality of patient information.

A SSESSING R ISK OF S EXUAL HIV A CQUISITION Because offering PrEP is currently indicated for MSM at substantial risk of HIV acquisition, it is important to consider that although 76% of MSM surveyed in 2008 in 21 US cities reported a health care visit during the past year34, other studies reported that health care providers do not ask about, and patients often do not disclose, same-sex behaviors35. Box A1 contains a set of brief questions designed to identify men who are currently having sex with men and to assess a key set of sexual practices that are associated with the risk of HIV acquisition. In studies to develop scored risk indexes predictive of incident HIV infection among MSM36,37 (see Providers’ Supplement, Section 5), several critical factors were identified. B OX A1: R ISK B EHAVIOR A SSESSMENT FOR MSM 36 In the past 6 months:      

Have you had sex with men, women, or both? (if men or both sexes) How many men have you had sex with? How many times did you have receptive anal sex (you were the bottom) with a man who was not wearing a condom? How many of your male sex partners were HIV-positive? (if any positive) With these HIV-positive male partners, how many times did you have insertive anal sex (you were the top) without you wearing a condom? Have you used methamphetamines (such as crystal or speed)?

Box A2 contains a set of brief questions designed to identify women and men who are currently having sex with opposite-sex partners (heterosexually active) and to assess a key set of sexual practices that are associated with the risk of HIV acquisition as identified both in PrEP trials and epidemiologic studies38-40.

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B OX A2: R ISK B EHAVIOR A SSESSMENT FOR H ETEROSEXUAL M EN AND W OMEN In the past 6 months:     

Have you had sex with men, women, or both? (if opposite sex or both sexes) How many men/women have you had sex with? How many times did you have vaginal or anal sex when neither you nor your partner wore a condom? How many of your sex partners were HIV-positive? (if any positive) With these HIV-positive partners, how many times did you have vaginal or anal sex without a condom?

In addition, for all sexually active patients, clinicians may want to consider reports of diagnoses of bacterial STIs (chlamydia, syphilis, gonorrhea) during the past 6 months as evidence of sexual activity that could result in HIV exposure. For heterosexual women and men, sex without a condom (or its correct use) may also be indicated by recent pregnancy of a female patient or sexual partner of a male patient. Clinicians should also briefly screen all patients for alcohol abuse41 (especially before sexual activity) and the use of illicit non-injection drugs (e.g., amyl nitrite, stimulants).42,43 The use of these substances may affect sexual risk behavior44, hepatic or renal health, or medication adherence, any of which may affect decisions about the appropriateness of prescribing PrEP medication. In addition, if substance abuse is reported, the clinician should provide referral for appropriate treatment or harm-reduction services acceptable to the patient. Lastly, clinicians should consider the epidemiologic context of the sexual practices reported by the patient. The risk of HIV acquisition is determined by both the frequency of specific sexual practices (e.g., unprotected anal intercourse) and the likelihood that a sex partner has HIV infection. The same behaviors when reported as occurring in communities and demographic populations with high HIV prevalence or occurring with partners known to have HIV infection, are more likely to result in exposure to HIV and so will indicate greater need for intensive riskreduction methods (PrEP, multisession behavioral counseling) than when they occur in a community or population with low HIV prevalence (see http://www.AIDSvu.org or http://www.cdc.gov/nchhstp/atlas/). After assessing the risk of HIV acquisition, clinicians should discuss with the patient which of several effective prevention methods (e.g., PrEP, behavioral interventions)45 will be pursued. When supporting consistent and correct condom use is feasible and the patient is motivated to achieve it, high levels of protection against both HIV and several STIs46,47 are afforded without the side effects or cost of medication. A clinician can support consistent condom use by providing brief clinical counseling (see Providers’ Supplement, Section 7), by referring the patient to behavioral medicine or health education staff in the clinical setting, or by referring the patient to community-based or local health department counseling and support services. Preexposure Prophylaxis for the Prevention of HIV Infection in the United States – 2014 Clinical Practice Guideline

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Reported consistent (“always”) condom use is associated with an 80% reduction in HIV acquisition among heterosexual couples48. However, inconsistent condom use is less effective,37,49 and studies have reported low rates of recent consistent condom use among MSM50 and other sexually active adults51. Especially low rates have been reported when condom use was measured over several months rather than during most recent sex or the past 30 days52. Therefore, unless the patient reports confidence that consistent condom use can be achieved, additional HIV prevention methods, including the consideration of PrEP should be provided while continuing to support condom. A patient who reports that 1 or more regular sex partners is of unknown HIV status should be offered HIV testing for those partners, either in the clinician’s practice or at a confidential testing site (see zip code lookup at http://www.hivtest.org/). Lastly, for any regular sex partner reported to be HIV-positive, clinicians should determine whether the partner is receiving antiretroviral therapy and whether a recent evaluation indicates an undetectable viral load. In addition to the known health benefits of viral load suppression, a recent clinical trial (HPTN 05253) demonstrated that viral load suppression is highly, but not completely, protective against HIV transmission to a heterosexual partner (96% reduction). No similar trial has been done with MSM in HIV-discordant couples, so it is unknown how much viral load suppression reduces HIV transmission among partners who are MSM. Persons who know they have HIV infection may not be in care, may not be receiving antiretroviral therapy, may not be receiving highly effective regimens, may not be adherent to their medications, or for other reasons may not have viral loads that are associated with the least risk of transmission to an uninfected sex partner54. B OX B1: R ECOMMENDED INDICATIONS FOR P R EP U SE BY MSM 2    

Adult man Without acute or established HIV infection Any male sex partners in past 6 months (if also has sex with women, see Box B2) Not in a monogamous partnership with a recently tested, HIV-negative man AND at least one of the following

  

Any anal sex without condoms (receptive or insertive) in past 6 months Any STI diagnosed or reported in past 6 months Is in an ongoing sexual relationship with an HIV-positive male partner

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B OX B2: R ECOMMENDED INDICATIONS FOR P R EP U SE BY H ETEROSEXUALLY A CTIVE M EN AND W OMEN    

Adult person Without acute or established HIV infection Any sex with opposite sex partners in past 6 months Not in a monogamous partnership with a recently tested HIV-negative partner AND at least one of the following

 



Is a man who has sex with both women and men (behaviorally bisexual) [also evaluate indications for PrEP use by Box B1 criteria] Infrequently uses condoms during sex with 1 or more partners of unknown HIV status who are known to be at substantial risk of HIV infection (IDU or bisexual male partner) Is in an ongoing sexual relationship with an HIV-positive partner

A SSESSING R ISK OF HIV A CQUISITION T HROUGH I NJECTION P RACTICES Although the annual number of new HIV infections among IDU in the United States has declined, a sizable number occur each year. In 2010, IDUs accounted for 8% of estimated incident HIV infections55. According to the National HIV Behavioral Surveillance System (NHBS)56 substantial proportions of IDU report sharing syringes (34%) and sharing injection equipment (58%). In addition, in NHBS and epidemiologic studies conducted with IDU, most IDU report sexual behaviors that also confer risk of HIV acquisition57. Because of the efficacy and safety demonstrated in the PrEP trial with IDU, providing PrEP to those who report injection behaviors that place them at substantial risk of acquiring HIV infection could contribute to HIV prevention for IDU at both the individual and the population level. Although current evidence is insufficient for a recommendation that all patients be screened for injection or other illicit drug use, the US Preventive Services Task Force recommends that clinicians be alert to the signs and symptoms of illicit drug use in patients.26 Clinicians should determine whether patients who are currently using illicit drugs are in (or want to enter) behavioral, medication-assisted, or in-patient drug treatment. For persons with a history of injecting illicit drugs but who are currently not injecting, clinicians should assess the risk of relapse along with the patients’ use of relapse prevention services (e.g., a drug-related behavioral support program, use of mental health services, 12-step program). Box A3 contains a set of brief questions that may help identify persons who are injecting illicit drugs, and to assess a key set of injection practices that are associated with the risk of HIV acquisition as identified in the PrEP trial with IDU5 and in epidemiologic studies56,58.

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B OX A3: R ISK B EHAVIOR A SSESSMENT FOR INJECTION D RUG U SERS    

Have you ever injected drugs that were not prescribed to you by a clinician? (if yes), When did you last inject unprescribed drugs? In the past 6 months, have you injected by using needles, syringes, or other drug preparation equipment that had already been used by another person? In the past 6 months, have you been in a methadone or other medication-based drug treatment program?

B OX B3: R ECOMMENDED INDICATIONS FOR P R EP U SE BY INJECTION D RUG U SERS   

Adult person Without acute or established HIV infection Any injection of drugs not prescribed by a clinician in past 6 months AND at least one of the following

  

Any sharing of injection or drug preparation equipment in past 6 months Been in a methadone, buprenorphine, or suboxone treatment program in past 6 months Risk of sexual acquisition (also evaluate by criteria in Box B1 or B2)

PrEP or other HIV prevention should be integrated with prevention and clinical care services for the many health threats IDU may face (e.g., hepatitis B and C infection, abscesses, septicemia, endocarditis, overdose)59. In addition, referrals for drug treatment, mental health services, and social services may be indicated59.

L ABORATORY T ESTS AND O THER D IAGNOSTIC P ROCEDURES All patients whose sexual or drug injection history indicates consideration of PrEP and who are interested in taking PrEP must undergo laboratory testing to identify those for whom this intervention would be harmful or for whom it would present specific health risks that would require close monitoring. HIV

TESTING

HIV testing and the documentation of results are required to confirm that patients do not have HIV infection when they start taking PrEP medications. For patient safety, HIV testing and should be repeated at least every 3 months (before prescriptions are refilled or reissued). This requirement should be explained to patients during the discussion about whether PrEP is appropriate for them. The Centers for Disease Control and Prevention (CDC) and the US Preventive Services Task Force recommends that MSM, IDUs, patients with a sex partner who has HIV infection, and others at substantial risk of HIV acquisition undergo an HIV test at least annually or for those Preexposure Prophylaxis for the Prevention of HIV Infection in the United States – 2014 Clinical Practice Guideline

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with additional risk factors, every 3-6.60 However, outside the context of PrEP delivery, testing is often not done as frequently as recommended.61 At a minimum, clinicians should document a negative antibody test result within the week before initiating (or reinitiating) PrEP medications. The required HIV testing can be accomplished by (1) drawing blood (serum) and sending the specimen to a laboratory for a routine HIV EIA (enzyme-linked immunoassay) or (2) performing a rapid, point-of-care, FDA-approved, fingerstick blood test. Oral rapid tests should not be used to screen for HIV infection when considering PrEP use because they can be less sensitive than blood tests 1,21,62. Clinicians should not accept patient-reported test results or documented anonymous test results. A preliminary positive HIV antibody test must be confirmed by Western blot or IFA (immunofluorescence assay) according to the local laboratory standard practice63 and viral load and CD4 lymphocyte tests should be ordered to assist in future treatment decisions. See Appendix 1 for Tables 11 - 12 for FDA-approved HIV tests, specimen requirements, and time to detection of HIV infection64. A CUTE HIV I NFECTION In the iPrEx trial, drug-resistant virus developed in 2 persons with unrecognized acute HIV infection at enrollment and for whom TDF/FTC had been dispensed. These participants had negative antibody test results before they started taking PrEP, tested positive at a later study visit, and PCR (polymerase chain reaction) on stored specimens from the initial visit detected the presence of virus. When questioned, most of the 10 acutely infected participants (8 of whom had been randomly assigned the placebo group) reported signs and symptoms consistent with a viral syndrome2. Both acutely infected patients to whom TDF/FTC had been dispensed had the M184V/I mutation associated with emtricitabine resistance, but not the K65R mutation associated with tenofovir resistance2. Among participants who were dispensed PrEP medication in the US MSM Safety Trial and in the Partners PrEP, TDF2, and VOICE trials (see Table 6), the M184V mutation, developed in several persons who were enrolled and had started taking medication with unrecognized acute HIV infection but K65R developed in only one (in the TDF2 study). However, no mutations emerged in persons who acquired infection after baseline. In the one trial with very low medication adherence that has published its resistance testing results, the emtricitabine resistance mutation, but not the K65R mutation was found in a few persons with incident infection after baseline (4 persons in the FEM-PrEP trial). PrEP is indicated for MSM, heterosexual men and women, and IDUs who report injection or sexual behaviors that place them at substantial risk of HIV acquisition. Therefore clinicians should suspect acute HIV infection in persons known to have been exposed recently (e.g., a condom broke during sex with an HIV-infected partner, relapse to injection drug use with shared injection equipment). In addition, clinicians should solicit a history of nonspecific signs or

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symptoms of viral infection during the preceding month or on the day of evaluation (Table 7) in all PrEP candidates with a negative or an indeterminate result on an HIV antibody test. Table 7: Clinical Signs and Symptoms of Acute (Primary) HIV Infection 65 Sex Route of transmission

Features (%) Fever Fatigue Myalgia Skin rash Headache Pharyngitis Cervical adenopathy Arthralgia Night sweats Diarrhea

Overall

Male

Female

(n = 375)

(n = 355)

(n = 23)

Sexual (n = 324)

75 68 49 48 45 40 39 30 28 27

74 67 50 48 45 40 39 30 28 27

83 78 26 48 44 48 39 26 22 21

77 71 52 51 47 43 41 28 30 28

Injection Drug Use (n = 34) 50 50 29 21 30 18 27 26 27 23

An additional blood specimen should be tested for any patient who has a negative or indeterminate result from a rapid HIV test or laboratory HIV antibody test, and who reports recent signs and symptoms suggestive of acute HIV. See the Figure below for the testing algorithm recommended for the documentation of HIV infection status before the initiation of PrEP or its re-initiation after more than a week off PrEP medication.

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Figure Documenting HIV Status

R ENAL

FUNCTION

In addition to confirming that any person starting PrEP medication is not infected with HIV, a clinician should determine renal function and test for infection with hepatitis B virus (HBV) because both decreased renal function and active HBV infection are potential safety issues for the use of TDF/FTC as PrEP. TDF is widely used in combination antiretroviral regimens for the treatment of HIV infection66. Among HIV-infected persons prescribed TDF-containing regimens, decreases in renal function (as measured by estimated creatinine clearance [eCrCl]) have been documented, and occasional cases of acute renal failure, including Fanconi’s syndrome, have occurred67,-69. In the PrEP trials among otherwise healthy, HIV-uninfected adults, an eCrCl of ≥60 ml/min was an eligibility criterion. Safety data for TDF/FTC prescribed to persons with reduced renal function are not available. Therefore, for all persons considered for PrEP, a serum creatinine test

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should be done, and an eCrCL should be calculated by using the Cockcroft-Gault formula (see Box C). Any person with an eCrCl of 2 (5 (

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